The emergence of addictive patterns of drug-seeking behavior is thought to arise from persistent neuroadaptations in mesolimbic dopaminergic circuitry during acquisition and corticostriatal glutamatergic circuitry during relapse. Neuroplasticity along these pathways can be regulated by a host of genetic and proteomic factors, including members of the neurotrophic factor family. In particular, brain-derived neurotrophic factor (BDNF) has been characterized as an essential regulator of neuroplasticity underlying learning and memory (Tyler et al., 2002), goal-oriented, and motivated behaviors (Nestler and Carlezon, 2006), and addictive cocaine seeking (Shaham &Hope, 2005) along mesolimbic and corticostriatal pathways. Direct intracranial infusion of exogenous BDNF into the dorsomedial prefrontal cortex (dmPFC), an origin for many glutamatergic corticostriatal projections, attenuates cocaine-seeking 22 hrs postinfusion, and for up to 21 days in tests of cue-induced and cocaine prime-induced reinstatement of cocaine seeking. However, the mechanisms by which intra-dmPFC BDNF modulates the expression of cocaine seeking at the 22 hr time point have not been adequately characterized. The current study addresses this knowledge gap by examining whether signaling in the MAPK and PI3K intracellular cascades underlie the suppressive effect of intra-dmPFC BDNF on cocaine-seeking 22 hrs postinfusion. It is hypothesized that downstream signaling along plasticity-related intracellular cascades in dmPFC neurons is required for a BDNF-mediated suppression of cocaine seeking to be expressed. Using selective inhibitors of MEK and PI3K in the dmPFC, we aim to assess the contribution of these cascades to BDNF's suppressive effect on cocaine seeking during extinction 22 hrs postinfusion. Immunological detection methods will verify antagonist efficacy, as well as characterize the dmPFC phosphoprotein response to cocaine self-administration and exogenous BDNF's regulation of MAPK and PI3K activation. The overarching goal will be to identify the neurobiological substrates by which BDNF regulates cocaine-induced neuronal plasticity in the dmPFC and NAc. The finding that BDNF regulates the propensity to engage in addictive drug seeking suggests that neurotrophins should be examined as novel therapeutic targets to prevent relapse to cocaine seeking in human patients. Given the paucity of pharmacotherapies that successfully prevent craving and relapse to cocaine taking, the prospect of intervening in the BDNF system is relevant to public health because of the potential to prevent cocaine-induced neuronal plasticity and addictive cocaine-seeking.